Treatment of pain, fever, and inflammation with compositions containing piperidinobutan-and 3-buten-2-ones

ABSTRACT

A method of treating pain, fever, and inflammation and pharmaceutical compositions for use therein, wherein the active ingredient comprises a compound of the formula;     &lt;IMAGE&gt;  (I.)  &lt;IMAGE&gt; (II.) +TR &lt;IMAGE&gt; (III.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is concerned with certain novel compounds, andwith a novel method of treating pain, fever, and inflammation and novelcompositions for use therein containing as an active ingredient, apiperidinobutan- or 3-buten-2-one compound.

2. Brief Description of the Prior Art

Various piperidinobutan- and 3-buten-2-ones used in the method andcompositions of the present invention are disclosed in U.S. Pat. No.4,145,426 and Dybas et al, Development in Industrial Microbiology, Vol.19, pp. 347-353 (1978). However, they are described therein as beinguseful in a process for protecting materials of various kinds againstinfection and damage by microorganisms, as by bacteria and fungi, and,thus, the method and compositions of the present invention are notsuggested.

SUMMARY OF THE INVENTION

The present invention provides novel compounds of the formula: ##STR2##wherein

R₃ and R₄ are selected from hydrogen; C₁₋₃ alkyl; C₂₋₃ alkenyl; hydroxy;hydroxy C₁₋₃ alkyl; phenyl; carboxyl; carboxamido; C₁₋₄ N-mono- andN,N-disubstituted carbonylamino; C₁₋₄ alkoxycarbonyl; 1-pyrrolidinyl;and 1-piperidinyl;

A is ##STR3## and n is 0 to 3; and acid addition and quaternary saltsthereof.

An example of a preferred compound of the present invention is3,3'-[1,3-propanediylbis-(4,1-piperidinediyl)bis(methylene)bis[3-buten-2-one].

In accordance with the present invention there is also provided a methodof treating pain, fever, and inflammation comprising administering to ahost in need of such treatment a therapeutically effective amount of acompound of the formula: ##STR4## wherein

R₁ and R₂ are independently selected from hydrogen; C₁₋₈ alkyl; C₂₋₈alkenyl; hydroxy C₁₋₈ alkyl; and cyclo C₄₋₈ alkyl; or R₁ and R₂ takentogether with the nitrogen atom form a five- or six-membered saturatedheterocyclic ring substituted at the 2-, 3-, and 4- position with R₃,R₄, and R₅, respectively;

R₃, R₄, and R₅ are selected from hydrogen; C₁₋₃ alkyl; C₂₋₃ alkenyl;hydroxy; hydroxy C₁₋₃ alkyl; phenyl; carboxyl; carboxamido; C₁₋₄ alkylN-mono- and N,N-disubstitutedcarbonylamino; C₁₋₄ alkoxycarbonyl;1-pyrrolidinyl; and 1-piperidinyl;

A is ##STR5## and n is 0 to 3; and acid addition and quaternary saltsthereof.

Examples of preferred compounds for use in the novel pharmaceuticalcompositions and method of treatment of the present invention are:

3-(1-piperidinylmethyl)-3-buten-2-one;

4-(4-hydroxy-1-piperidinyl)-3-[(4-hydroxy-1-piperidinyl)methyl]buten-2-one

3,3'-[1,3-propanediylbis(4,1-piperidinediyl)bis(methylene)]bis[3-buten-2-one]

3-[(3-carbamylpiperidino)methyl]-4-(3-carbamylpiperidino)butan-2-oneadipate

3-[(4-carboxypiperidino)methyl]-4-(4-carboxypiperidino)butan-2-one

3-[(3-hydroxymethylpiperidino)methyl]-4-(3-hydroxymethylpiperidino)buten-2-one

The present invention also provides pharmaceutical compositions fortreating a condition exhibiting at least one of the symptoms of pain,fever, and inflammation, comprising a pharmaceutically acceptable,non-toxic carrier, and a therapeutically effective amount of a compoundof Formulas I, II, or III as described above.

The compounds of Formula I useful in the method and compositions of thepresent invention may be synthesized by techniques involving thecondensation of 2-, 3-, or 4-substituted piperidines, formaldehyde, andacetone, as illustrated in the following reaction scheme: ##STR6##

The olefinic elimination products of Formula II may be obtained from thecompounds synthesized by the procedures shown in A. above, using avariety of methods such as with heat, salt formation with oxalic acid,by steam distillation to cite some, as illustrated in the followingreaction scheme: ##STR7##

Several routes are suitable for the synthesis of the compounds ofFormula I wherein the two base substituents are different. Themono-Mannich base may be prepared as follows: ##STR8## and reacted witha second mole of formaldehyde and secondary amine: ##STR9## A mole ofamine may be added to the olefin of Formula II: ##STR10## Or, thevarious sequences outlined may employ the secondary amine, ##STR11##initially to produce the bis-Mannich derivative. Elimination of one moleof amine then provides the following compounds: ##STR12## Addition ofone mole of ##STR13## forms compounds of Formula I.

The compounds of Formula I which contain identical substitutedpiperidine groups are prepared by reacting substantially molar ratios of2:1:2 with respect to amine, acetone and formaldehyde. A considerableexcess of the first and/or third reaction component may be used.

A variety of solvents may be used for the synthesis including water,alcohols, ethers as well as an excess of one of the reagents other thanacetone. The amines can be used in the Mannich reaction as free bases orin the form of salts such as the acetate or hydrochloride. Generally,elevated temperatures are required in the range of 45° C. to 110° C. andreaction periods of from 1 to 24 hours. Isolation of products may beaccomplished by crystallization or distillation. Any other chemicalgroupings present in the organic bases employed for the Mannich reactionwhich contain active hydrogen should preferably be blocked andafterwards liberated by techniques well known in the art.

The addition reactions of Formula II olefinic compounds with amines toprovide Formula I derivatives may be run with a 1:1 molar ratio ofreactants in solvents such as water, alcohols, dioxane or mixtures ofthese or neat. Generally, no heat is required and reaction times mayrange from 1/2 to 10 hours. The course of the reaction is readilymonitored by measuring the disappearance of the alpha beta unsaturatedketonic moiety as with ultraviolet or infra-red spectral analysis.

The compounds of Formula III may be prepared in accordance with theprocedures described above for preparing the compounds of Formulas I andII, substituting for the piperidines employed therein, the appropriatedipiperidine compound.

Both Formula I and Formula II compounds can be used in the form of saltsderived from inorganic or organic acids. Included among such salts arethe following: acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butylrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained.

The piperidinobutan- and 3-buten-2-ones of the present invention possessa high degree of anti-inflammatory, analgesic and anti-pyretic activity.They are of value in the treatment of arthritic and dermatologicaldisorders or like conditions responsive to anti-inflammatory drugs. Ingeneral they are indicated for a wide variety of conditions where one ormore of the symptoms of inflammation, fever and pain are manifested.Included within this category are diseases such as rheumatoid arthritis,osteo arthritis, gout, infectious arthritis and rheumatic fever. Asindicated above the compounds utilized in the practice of the inventionalso possess a useful degree of analgesic and anti-pyretic activity.

For these purposes the compounds of the present invention may beadministered orally, topically, parenterally, by inhalation spray orrectally in dosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques. Inaddition to the treatment of warm-blooded animals such as mice, rats,horses, dogs, cats, etc., the compounds of the invention are effectivein the treatment of humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide a pharmaceutically elegant andpalatable preparation. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for manufacture of tablets. These excipients may be, forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example maize starch, or alginic acid;binding agents, for example starch, gelatine or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

Formulations for oral use may also be presented as hard gelatinecapsules wherein the active ingredient is mixed with an inert soliddiluent, for example calcium carbonate, calcium phosphate or kaolin, oras soft gelatine capsules wherein the active ingredient is mixed withwater or an oil medium, for example arachis oil, peanut oil, liquidparaffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a natural-occurring phosphatide, forexample, lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol mono-oleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyoxyethylene sorbitanmono-oleate. The said aqueous suspensions may also contain one or morepreservatives, for example, ethyl or n-propyl p-hydroxy benzoate, one ormore coloring agents, one or more flavoring agents and one or moresweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilsuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of anantioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oils, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soya bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan mono-oleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan mono-oleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative and flavouring and colouring agents. Thepharmaceutical compositions may be in the form of a sterile injectablepreparation, for example as a sterile injectable aqueous or oleagenoussuspension. This suspension may be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation mayalso be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectibles.

The compounds of this invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc. containing the anti-inflammatory agents are employed.

Dosage levels of the order of 20 mg. to 1 gram per day are useful in thetreatment of the above indicated conditions. For example, inflammationis effectively treated and anti-pyretic and analgesic activitymanifested by the administration of from about 0.3 to 60 milligrams ofthe compound per kilogram of body weight per day. Advantageously fromabout 2 mg. to about 30 mg. per kilogram of body weight and especiallyfrom about 4 mg. to about 20 mg./kg. per daily dosage produce highlyeffective results.

The amount of active ingredient that may be conbined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 5 mg. to 1 gram of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 25 mg. to about 500 mg. of activeingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variey of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

The following examples will serve to illustrate preparation of thecompounds used in the method of treatment and pharmaceuticalcompositions of the present invention, without, however, limiting thescope thereof.

EXAMPLE 13-[(4-Hydroxypiperidino)methyl]-4-(hydroxypiperidino)butan-2-one

A solution of 4-hydroxypiperidine (20.5 g.) in 40 ml. of water ischilled in an ice bath and mixed with acetone (30 ml.) and potassiumchloride (15.1 g.). After complete solution there is added dropwise overa 15-minute period formaldehyde, aqueous 35% (18 ml.). The reactionmixture was then stirred 12 hr. at 20°-25° C. It was made alkaline with50% sodium hydroxide aqueous solution and the resultant two phasesseparated. The aqueous layer was cooled and extracted several times withmethylene chloride. The combined organic phase and methylene chlorideextracts were washed with saturated sodium chloride solution and thendried over anhydrous sodium sulfate. After filtration the solvent wasstripped under reduced pressure leaving an oil, 24.2 g. Its massspectrum showed a molecular ion of 183, the infrared and nuclearmagnetic resonance proton spectra were in agreement for the product.

In place of 4-hydroxypiperidine the following substituted piperidinesmay be reacted using the above procedure with formaldehyde and acetoneto provide the indicated products.

    ______________________________________                                        Piperidine Substituent                                                                       Product                                                        ______________________________________                                        1. 3-Hydroxy   3-[(3-Hydroxypiperidino)methyl]-                                              4-(3-hydroxypiperidino)butan-                                                 2-one                                                          2. 3-Hydroxymethyl                                                                           3-[(3-Hydroxymethylpiperidino)-                                               methyl]-4-(3-hydroxymethyl-                                                   piperidino)butan-2-one                                         3. 4-Carboxy   3-[(4-Carboxypiperidino)-                                                     methyl]-4-(4-carboxypiperi-                                                   dino)-butan-2-one                                              4. 3-Carbamyl  3-[(3-Carbamylpiperidino)methyl]-                                             4-(3-carbamylpiperidino)-                                                     butan-2-one                                                    5. 4-(N-Methylcarbamyl)                                                                      3-{[4-(N-Methylcarbamyl)piperi-                                               dino]methyl}-4-[4-(N-methyl-                                                  carbamyl)piperidino]butan-2-                                                  one                                                            6. 4-Ethoxycarbonyl                                                                          3-[(4-Ethoxycarbonylpiperidino)-                                              methyl]-4-(4-ethoxypiperidino)-                                               butan-2-one                                                    7. 4-Isopropyl 3-[(4-Isopropylpiperidino)-                                                   methyl]-4-(4-isopropyl-                                                       piperidino)butan-2-one                                         8. 3-Methyl-4- 3-[(3-Methyl-4-hydroxymethyl-                                  hydroxymethyl  piperidino)methyl]-4-(3-                                                      methyl-4-hydroxymethyl-                                                       piperidino)butan-2-one                                         9. 4-Phenyl-4-hydroxy                                                                        3-[(4-Phenyl-4-hydroxypiperi-                                                 dino)methyl]-4-(4-phenyl-4-                                                   hydroxypiperidino)butan-2-                                                    one                                                            10. 4-(Piperidino)                                                                           3-{[4-(Piperidino)piperidino]-                                                methyl}-4-[4-(piperidino)-                                                    piperidino]butan-2-one                                         Unsaturated Product                                                                          3-{[4-(Piperidino)piperidino]-                                                methyl}-3-buten-2-one                                          11. 4-(Pyrrolidino)                                                                          3-{[4-(Pyrrolidino)piperidino]-                                               methyl}-4-[ 4-(pyrrolidino)pip-                                               eridino]butan-2-one                                            Unsaturated Product                                                                          3-{[4-(Pyrrolidino)piperidino]-                                               methyl}-3-buten-2-one                                          12. 2-n-Butylpiperidine                                                                      3-[(2-n-Butylpiperidino)-                                                     methyl]-4-(2-n-butylpiperi-                                                   dino)butan-2-one                                               ______________________________________                                    

Di-Hydrochloride of3-[(4-Hydroxypiperidino)methyl]-4-(4-hydroxypiperidino)-butan-2-one

The title ketone (2.84 g., 0.01 mole) is dissolved in 50 ml. of dryether and reacted with dry hydrogen chloride until no furtherprecipitation. The product after aging in the mother liquor isseparated, washed with ether and dried at 40° C. under reduced pressure.

EXAMPLE 2 3-[(4-Hydroxypiperidino)methyl]-3-buten-2-one

3-[(4-Hydroxypiperidino)methyl]-4-(4-(hydroxypiperidino)butan-2-one (1g.) was dissolved in 8 ml. of ethyl alcohol and added to a cooledsolution of oxalic acid anhydrous (0.9 g.) in 5 ml. of ethyl alcohol.After standing at 0° C. for five minutes, the resultant precipitate wasfiltered. The filtrate was stripped of solvent under reduced pressureand the residual oil taken up in a small volume of water, saturated withpotassium carbonate and then extracted with ether. The ether solutionwas dried over anhydrous sodium sulphate, filtered and the filtratestripped of ether. The residual oil, approximately 0.1 g., wascharacterized including a proton nuclear magnetic resonance spectrum indeuterated dimethylsulfoxide. There were two vinylic protons, at 5.9 and6.1 ppm downfield from the reference tetramethylsilane.

Additional 3-[substituted piperidinomethyl]-3-buten-2-ones are preparedby this procedure and include

    ______________________________________                                        Product           Unsaturated Product                                         ______________________________________                                        3-[(3-Hydroxypiperidino)                                                                        3-[(3-Hydroxypiperidino)-                                   methyl]-4-(3-hydroxy-                                                                           methyl]-3-buten-2-one                                       piperidino)butan-2-one                                                        3-[(3-Hydroxymethyl-                                                                            3-[(3-hydroxymethylpiper-                                   piperidino)methyl]-4-(3-                                                                        idino)methyl]-3-buten-2-                                    hydroxymethylpiperidino)                                                                        one                                                         butan-2-one                                                                   3-[(4-Carboxypiperidino)                                                                        3[(4-Carboxypiperidino)-                                    methyl]-4-(4-carboxy-                                                                           methyl]-3-buten-2-one                                       piperidino)butan-2-one                                                        3-[(3-Carbamylpiperidino)                                                                       3-[(3-Carbamylpiperidino)-                                  methyl]-4-(3-carbamyl-                                                                          methyl]-3-buten-2-one                                       piperidino)butan-2-one                                                        3-{[4-(N-methylcarbamyl)-                                                                       3-{[4-(N-Methylcarbamyl)                                    piperidino]methyl}-4-[4-                                                                        piperidino]methyl}-3-                                       (N-methylcarbamyl)piper-                                                                        buten-2-one                                                 idino]butan-2-one                                                             3-[(4-Ethoxycarbonylpiperi-                                                                     3-[(4-Ethoxycarbonyl-                                       dino)methyl]-4-(3-ethoxy-                                                                       piperidino)methyl]-3-                                       piperidino)butan-2-one                                                                          buten-2-one                                                 3-[(4-Isopropylpiperidino)-                                                                     3-[(4-Isopropylpiperi-                                      methyl]-4-(4-isopropyl-                                                                         dino)methyl]-3-buten-2-                                     piperidino)butan-2-one                                                                          one                                                         3-[(3-Methyl-4-hydroxy-                                                                         3-[(3-Methyl-4-hydroxy-                                     methylpiperidino)methyl]-                                                                       methylpiperidino)methyl]-                                   4-(3-methyl-4-hydroxy-                                                                          3-buten-2-one                                               methylpiperidino)butan-2-                                                     one                                                                           3-[(4-Phenyl-4-hydroxy-                                                                         3-[(4-Phenyl-4-hydroxy-                                     piperidino)methyl]-4-(4-                                                                        piperidino)methyl]-3-                                       phenyl-4-hydroxypiperi-                                                                         buten-2-one                                                 dino)-butan-2-one                                                             ______________________________________                                    

Methiodide Quaternary Salt of3-[(4-hydroxypiperidino)methyl]-3-buten-2-one

The olefinic basic ketone (1.83 g., 0.01 mole) is dissolved in 25 ml. ofdry ether and mixed with 0.7 ml. of methyl iodide. After stirringovernight an additional 1 ml. of methyl iodide is added and anadditional 12 hr. of reaction time is employed. The separated product iswashed repeatedly with dry ether and dried.

Benzyl Bromide Quaternary Salt

The basic ketone (1.83 g., 0.01 mole) is dissolved in 15 ml. of acetoneand mixed with benzyl bromide (1.9 g., 0.011 mole). The solution isheated in a bath at 70° C. for 12 hr. The solid product is separated,washed with acetone followed by ether and then dried at 45° C. undervacuum.

EXAMPLE 3 3-Diethylaminomethyl-4-(4-hydroxypiperidino)butan-2-one

Step A. 1,1-Bis(Diethylaminomethyl)acetone

This compound was prepared in the manner described in J.A.C.S. 65, 972(1943) by adding a solution of 210 ml. diethylamine in 400 ml. water to300 ml. acetone, to which was then added without cooling 170 ml. 37%aqueous formaldehyde solution. The reaction evolved heat, and afterstanding 16 hours, the 2-phase reaction mixture was made alkaline by theaddition of dilute sodium hydroxide, the water phase saturated withsodium chloride and the upper oil phase separated. The brine layer wasextracted with three 400 ml. portions of ether; the ether extracts werecombined and joined with the oil. The ether solution was dried overmagnesium sulphate, and the solvent removed by distillation. Theresidual oil was fractionated by distillation under reduced pressure toyield the product, b.p. 103°-111°/6 ml.

The reaction was run similarly with the substitution of equimolarquantities of other organic bases in place of diethylamine, namely,dimethylamine, di-n-propylamine, di-isobutylamine, di-2-ethylhexylamine,diallylamine, piperidine and pyrrolidine. The isolation of the oilyreaction product was readily achieved by phase separation. Purification,if desired, could be achieved by fractional distillation or byfractional crystallization of the salts prepared in anhydrous alcohol orether with inorganic acids. The free bases containing twonitrogen-bearing groups substituted on the one carbon atom of theacetone molecule were high boiling oils of very slight color showinggenerally low water solubility and being readily soluble in the commonorganic solvents. Water-saturated solutions showed pH values above 10.

Step B. 3-Diethylaminomethylbut-3-en-2-one

The intermediate olefinic ketone is prepared by the procedure of H. M.E. Carwell [J. Chem. Soc., 1058 (1950)]. The ketone obtained from A.,22.8 g., in 25 ml. of ethanol was added to a solution of 25 g. ofanhydrous oxalic acid in 75 ml. of ethanol. The mixture was cooled to 0°C., filtered to remove diethylamine hydrogen oxalate and the motherliquor evaporated to dryness under reduced pressure. The residue wasdissolved in a little water, treated with potassium carbonate andextracted with ether. The ether was dried over anhydrous sodium sulphateand the residue obtained by solvent removal was distilled. Afterre-distillation the product was obtained as an oil, b.p. 82° C./18 mm.Similarly, the other 1,1-bis-(disubstituted aminomethyl)acetonesobtained as in A. can be converted to the corresponding 3-disubstitutedaminomethylbut-3-en-2-ones. The disubstituted amino term as previouslyindicated also comprises pyrrolidine and piperidine alicyclic ringanalogs. For example, 3-(piperidinomethyl)but-3-en-2-one boils at135°-139° C./15 mm. and is synthesized following the same procedure from1,1-bis(-piperidinomethyl)acetone.

The following are synthesized using this procedure:

    ______________________________________                                        Amine +    Unsaturated Product →                                                                  Product                                            ______________________________________                                        Dimethylamine                                                                            3-[(3-Hydroxypiperi-                                                                          3-Dimethylamino-                                              dinomethyl]-3-buten-                                                                          methyl-4-(3-                                       2-one      hydroxypiperi-                                                                                dino)butan-2-one                                   Di-n-octyl 3-[(3-Hydroxymethyl-                                                                          3-Di-n-octyl-                                      amine      piperidino)methyl]-3-                                                                         aminomethyl-4-                                                buten-2-one     (3-hydroxy-                                                                   methylpiperi-                                                                 dino)butan-2-                                                                 one                                                Ethanol-   3-[(4-carboxypiperi-                                                                          3-[(4-carboxy-                                     amine      dino)methyl]-3- piperidino)-                                                  buten-2-one     methyl]-4-(2-                                                                 hydroxyethyl-                                                                 amino)butan-2-                                                                one                                                Dicyclo-   3-[(3-carbamylpiperi-                                                                         3-[(3-carbamyl-                                    hexylamine dino)-methyl]-3-                                                                              piperidino)                                                   buten-2-one     methyl]-4-(dicy-                                                              clohexylamino)                                                                butan-2-one                                        Pyrrolidine                                                                              3-{[4-(N-methylcar-                                                                           3-{[4-(N-methyl-                                              bamyl)piperidinol]                                                                            carbamyl)piperi-                                              methyl}-3-buten-2-                                                                            dino]methyl}-4-                                               one             (pyrrolidino)                                                                 butan-2-one                                        Piperidine 3-[(4-ethoxycarbonyl-                                                                         3[(4-Ethoxy-                                                  piperidino)methyl]-                                                                           carbonylpiperi-                                               3-buten-2-one   dino)methyl]-4-                                                               (piperidino)                                                                  butan-2-one                                        2-Methyl-  3-[(3-Hydroxypiperi-                                                                          3-[(2-methyl-                                      piperidine dino)methyl]-3- piperidino)methyl]                                            buten-2-one                                                        4-(3-hydroxy-                                                                                            piperidino)butan-                                                             2-one                                              Diethanol- 3-[(4-Isopropylpiperi-                                                                        3-[di-(2-hydroxy-                                  amine      dino)methyl]-3- ethyl)aminomethyl]-                                           buten-2-one     4-(4-isopropyl-                                                               piperidino)butan-                                                             2-one                                              n-Hexylamine                                                                             3-[(3-methyl-4-hydroxy-                                                                       3-n-Hexylamino-                                               methylpiperidino)                                                                             methyl-4-(3-                                                  methyl]-3-buten-2-                                                                            methyl-4-hydroxy-                                             one             methylpiperidino)                                                             butan-2-one                                        Cyclopentyl-                                                                             3-[(4-Phenyl-4-hydroxy-                                                                       3-(Cyclopentyl-                                    amine      piperidino)methyl]-                                                                           aminomethyl)-4-                                               3-buten-2-one   (4-phenyl-4-                                                                  hydroxypiperi-                                                                dino)butan-2-                                                                 one                                                ______________________________________                                    

EXAMPLE 43,3'-[1,3-Propanediylbis(4,1-piperidinediyl)bis(methylene)]bis[3-buten-2-one]

A cold solution of acetone (3.7 ml.) and 37% aquous formaldehyde (8.9g.) was maintained at 4°-6° C., and then over an 8 minute periodbis[4,4'-(1,3- trimethylene)dipiperidine (5.26 g.) was added.Concentrated hydrochloric acid (5 ml.) was added dropwise over 20minutes to the resulting mixture, while the temperature was maintainedat 5°-10° C. The resulting solution was warmed to 20° C., stirred for 1hr. and then kept at 82° C. for 12 hr. The solution was then cooled inan ice bath, and at 15° C. or lower was made alkaline by gradualaddition of 1 ml. of sodium hydroxide (2 g. in 10 ml. of water). Anadditional 10 ml. of water was added and then 30 ml. of methylenechloride. The mixture was shaken and the resulting phases were separatedand the aqueous layer was again extracted with 30 ml. of methylenechloride. The combined organic extracts were dried with sodium sulfateand concentrated under reduced pressure to leave the product as a thickoil. The product NMR spectrum (CDCl₃) indicated 2 vinyl protons at 6.2ppm [(CH₃)₄ Si reference]; R_(F), 0.47 (10% ethanol in methylenechloride, SiO₂), and the molecular ion (mass spectrum) was in agreement.

EXAMPLE 5

A mixture of 250 parts of4-(4-hydroxy-1-piperidinyl)-3-[(4-hydroxy-1-piperidinyl)methyl]butan-2-onedihydrochloride and 25 parts of lactose is granulated with suitablewater, and to this is added 100 parts of maize starch. The mass ispassed through a 16 mesh screen. The granules are dried at a temperaturebelow 60° C. The dry granules are passed through a 16 mesh screen andmixed with 3.8 parts of magnesium stearate. They are then compressedinto tablets suitable for oral administration.

Using the same ingredients and procedures described above, butsubstituting for the butan-2-one as active ingredient the followingcompound:3,3'-[1,3-propanediylbis(4,1-piperidinediyl)bis(methylene)]bis[3-buten-2-one],there are prepared tablets suitable for oral administration.

The compound used in the foregoing example may be replaced by 25, 100,250, or 500 parts of piperidino butan-2-ones of this invention toproduce tablets suitable for oral administration as ananti-inflammatory, antipyretic and/or analgesic according to the methodof this invention.

EXAMPLE 6

A mixture of 50 parts of3-diethylaminomethyl-4-(4-hydroxypiperidino)butan-2-one pamoate, 3 partsof the calcium salt of lignin sulphonic acid, and 237 parts of water isball-milled until the size of substantially all particles of thecompound are less than 10 microns. The suspension is diluted with asolution containing 3 parts of sodium carboxymethylcellulose and 0.9parts of the butyl ester of p-hydroxy-benzoic acid in 300 parts ofwater. There is thus obtained an aqueous suspension suitable for oraladministration for therapeutic purposes.

EXAMPLE 7

A mixture of 250 parts of 1,1-bis(piperidinomethyl)propan-2-onesuccinate, 200 parts of maize starch and 30 parts of alginic acid ismixed with a sufficient quantity of a 10% aqueous paste of maize starch,and granulated. The granules are dried in a current of warm air and thedry granules are then passed through a 16-mesh screen, mixed with 6parts of magnesium stearate and compressed into tablet form to obtaintablets suitable for oral administration.

EXAMPLE 8

A mixture of 500 parts3-[(4-isopropylpiperidino)methyl]-4-(4-isopropylpiperidino)butan-2-onedihydrochloride, 60 parts maize starch and 20 parts of gum acacia isgranulated with a sufficient quantity of water. The mass is passedthrough a 12-mesh screen and the granules are dried in a current of warmair. The dry granules are passed through a 16-mesh screen, mixed with 5parts of magnesium stearate and compressed into tablet form suitable fororal administration.

EXAMPLE 9

(1) Tablets--10,000 scored tablets for oral use, each containing 100 mg.of piperidino-butan-2-one, are prepared from the following ingredients:

    ______________________________________                                                                  Gm.                                                 ______________________________________                                        3-[(3-carbamylpiperidino)methyl]-4-(3-carbamyl-                                                           1000                                              piperidino)butan-2-one adipate                                                Starch, U.S.P.              350                                               Talc, U.S.P.                250                                               Calcium stearate            35                                                ______________________________________                                    

The powdered adipate salt is granulated with a 4% w./v. aqueous solutionof methylcellulose U.S.P. (1500 cps.). To the dried granules is added amixture of the remainder of the ingredients and the final mixturecompressed into tablets of proper weight.

(2) Capsules--10,000 two-piece hard gelatin capsules for oral use, eachcontaining 50 mg. of the butan-2-one adipate are prepared from thefollowing ingredients:

    ______________________________________                                                                  Gm.                                                 ______________________________________                                        3-[(3-carbamylpiperidino)methyl]-4-(3-carbamyl-                                                           500                                               piperidino)butan-2-one adipate                                                Lactose, U.S.P.             1000                                              Starch, U.S.P.              300                                               Talc, U.S.P.                65                                                Calcium stearate            25                                                ______________________________________                                    

The powdered adipate salt is mixed with the starch-lactose mixturefollowed by the talc and calcium stearate. The final mixture is thenencapsulated in the usual manner. Capsules containing 10 and 25 mg. ofthe adipate salt are also prepared by substituting 100 and 250 gm. for500 gm. in the above formulation.

(3) Soft elastic capsules--One piece soft elastic capsules for oral use,each containing 50 mg. of3-[(3-carbamylpiperidino)methyl]-4-(3-carbamylpiperidino)butan-2-oneadipate are prepared in the usual manner by first dispersing thepowdered active material in sufficient corn oil to render the materialcapsulatable.

(4) Aqueous suspension--An aqueous suspension for oral use containing ineach 5 ml., 200 mg. of piperidino-butan-2-one, is prepared from thefollowing ingredients:

    ______________________________________                                                                  Gm.                                                 ______________________________________                                        3-[(3-carbamylpiperidino)methyl]-4-(3-carbamyl-                               piperidino)butan-2-one adipate                                                                            400                                               Methylparaben, U.S.P        7.5                                               Propylparaben, U.S.P.       2.5                                               Saccharin sodium            12.5                                              Glycerin, 3000 ml.                                                            Tragacanth powder           10                                                Orange oil flavor           10                                                F.D. and C. orange dye      7.5                                               Deionized water, q.s. to 10,000 gm.                                           ______________________________________                                    

What is claimed is:
 1. A method of treating a condition exhibiting atleast one of the symptoms of pain, fever, and inflammation, comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound of the formula: ##STR14## wherein R₁ andR₂ are independently selected from hydrogen; C₁₋₈ alkyl; C₂₋₈ alkenyl;hydroxy C₁₋₈ alkyl; and cyclo C₄₋ alkyl; or R₁ and R₂ taken togetherwith the nitrogen atom form a five- or six-membered saturatedheterocyclic ring substituted at the 2-, 3-, and 4-position with R₃, R₄,and R₅, respectively; andR₃, R₄, and R₅ are selected from hydrogen; C₁₋₃alkyl; C₂₋₃ alkenyl; hydroxy; hydroxy C₁₋₃ alkyl; phenyl; carboxyl;carboxamido; C₁₋₄ alkyl N-mono- and N,N-disubstituted carbonylamino;C₁₋₄ alkoxycarbonyl; 1-pyrrolidinyl; and 1-piperidinyl; and acidaddition and quaternary salts thereof.
 2. The method of claim 1 whereinthe compound is4-(4-hydroxy-1-piperidinyl-3-[(4-hydroxy-1-piperidinyl)methyl]butan-2-one.3. The method of claim 1 wherein the compound is3-[(3-carbamoylpiperidino)methyl]-4-(3-carbamylpiperidino)butan-2-oneadipate.
 4. The method of claim 1 wherein the compound is3-[(4-carboxypiperidino)methyl]-4-(4-carboxypiperidino)butan-2-one. 5.The method of claim 1 wherein the compound is3-[(3-hydroxymethylpiperidino)methyl]-4-(3-hydroxymethylpiperidino)butan-2-one.6. A pharmaceutical composition for treating a condition exhibiting atleast one of the symptoms of pain, fever, and inflammation, in unitdosage form suitable for oral administration selected from the groupconsisting of tablets, oily suspensions, soft and hard gelatinecapsules, syrups, and elixirs, comprising a pharmaceutically acceptable,non-toxic carrier, containing one or more agents selected from the groupconsisting of sweeting agents, flavoring agents, coloring agents, andpreserving agents, and a therapeutically effective amount of a compoundof the formula: ##STR15## wherein R₁ and R₂ are independently selectedfrom hydrogen; C₁₋₈ alkyl; C₂₋₈ alkenyl; hydroxy C₁₋₈ alkyl; and cycloC₄₋₈ alkyl; or R₁ and R₂ taken together with the nitrogen atom form afive- or six-membered saturated heterocyclic ring substituted at the 2-,3-, and 4-position with R₃, R₄ and R₅, respectively; andR₃, R₄, and R₅are selected from hydrogen; C₁₋₃ alkyl; C₂₋₃ alkenyl; hydroxy; hydroxyC₁₋₃ alkyl; phenyl; carboxyl; carboxamido; C₁₋₄ alkyl N-mono- andN,N-distituted carbonylamino; C₁₋₄ alkoxycarbonyl; 1-pyrrolidinyl; and1-piperidinyl; and acid addition and quaternary salts thereof.
 7. Thecomposition of claim 6 wherein the compound is4-(4-hydroxy-1-piperidinyl)-3-[(4-hydroxy-1-piperidinyl)methyl]butan-2-one8. The composition of claim 6 wherein the compound is3-[(3-carbamoylpiperidino)methyl]-4-(3-carbamoylpiperidino)butan-2-oneadipate.
 9. The composition of claim 6 wherein the compound is3-[(4-carboxypiperidino)methyl]-4-(4-carboxypiperidino)butan-2-one. 10.The composition of claim 6 wherein the compound is3-[(3-hydroxymethylpiperidino)methyl]-4-(3-hydroxymethylpiperidino)butan-2-one.